The knowledge that cancer cells rely on increased glycolysis rather than oxidative phosphorylation for survival is known as “The Warburg Hypothesis” (Warburg, O., Science, 123:309-314 (1956)). This concept constitutes the basis for using glycolysis and its associated enzymes as unique targets for the development of new anticancer therapeutic agents (Shaw, R. J., Curr. Opin. Cell Biol., 18:598-608 (2006); Gatenby, R. A. and Gillies, R. J., J. Biochem. Cell Biol., 39:1358-1366 (2007)). One such agent is 3-bromopyruvate (3-BrPA), a synthetic brominated derivative of pyruvic acid that acts as an irreversible glycolytic inhibitor (Ko et al., Cancer Lett., 173:83-91 (2001); Geschwind et al., Cancer Res., 62:3909-3913 (2002)). Early studies demonstrated that 3-BrPA is able to completely eradicate tumors implanted in rabbit livers when administered directly into the liver by intra-arterial injection, resulting in a significant survival benefit in advanced stages of the disease. The therapeutic dose was found to be to be 1.75 mM in 25 ml of phosphate-buffered saline (PBS), when given as a continuous, 1 hour intra-arterial infusion (Vali et al., J. Vasc. Interv. Radiol., 18:95-101 (2007)). Furthermore, when the animals were treated at a relatively early stage of their cancer, effective local control of the tumor resulted in the achievement of complete remission of the cancer. In addition to its excellent therapeutic profile, intra-arterially delivered 3-BrPA also had a favorable biodistribution profile with a high tumor uptake and no negative effects on healthy tissue (Vali et al., The Journal of Pharmacology and Experimental Therapeutics, 327(1):32-7 (2008)).
These results highlight that 3-BrPA is a highly promising anti-cancer agent. However, a major limitation for future clinical use of this compound is the fact that the preclinical testing was conducted using a rather uncommon delivery method for anti-cancer agents, i.e. intra-arterially directly into the liver. Because 3-BrPA is a non-specific alkylating agent, it is thought to be a highly toxic compound and it was believed that the intra-arterial approach was required to prevent systemic toxicities (Chang et al., Acad. Radiol., 14(1)85-92 (2007)).
Because intra-arterial administration is a technically challenging method for delivery an anti-cancer agent and is not applicable for every type of cancer, other 3-BrPA delivery methods are greatly desired.